Anatomy and Neurosciencehttp://hdl.handle.net/10468/559
Wed, 21 Feb 2018 10:39:19 GMT2018-02-21T10:39:19ZKynurenine pathway metabolism and neurobiology of treatment-resistant depression: Comparison of multiple ketamine infusions and electroconvulsive therapyhttp://hdl.handle.net/10468/5449
Kynurenine pathway metabolism and neurobiology of treatment-resistant depression: Comparison of multiple ketamine infusions and electroconvulsive therapy
Allen, Andrew P.; Naughton, M.; Dowling, J.; Walsh, A.; O'Shea, R.; Shorten, George D.; Scott, Lucinda V.; McLoughlin, D. M.; Cryan, John F.; Clarke, Gerard; Dinan, Timothy G.
Current first-line antidepressants can take weeks or months to decrease depressive symptoms. Low dose ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, shows potential for a more rapid antidepressant effect, with efficacy also evident in previously treatment-resistant populations. However, a greater understanding of the physiological mechanisms underlying such effects is required. We assessed the potential impact of ketamine infusion on neurobiological drivers of kynurenine pathway metabolism in major depression (HPA axis hyperactivity, inflammation) in patients with treatment-resistant depression compared to gender-matched healthy controls. Furthermore, we assessed these biomarkers before and after electroconvulsive therapy (ECT), which is currently the gold standard for management of treatment-resistant depression. As previously demonstrated, treatment with ketamine and ECT was associated with improved depressive symptoms in patients. At baseline, waking cortisol output was greater in the ECT cohort, kynurenine was greater in the ketamine cohort, and kynurenic acid was less in patients compared to healthy controls, although inflammatory markers (IL-6, IL-8, IL-10 or IFN-γ) were similar in patients and controls. Furthermore, in patients who responded to ECT, the cortisol awakening response was decreased following treatment. Despite a trend towards lesser kynurenine concentrations in those who responded to ketamine, ketamine was not associated with significant alterations in any of the biomarkers assessed.
Sat, 10 Feb 2018 00:00:00 GMThttp://hdl.handle.net/10468/54492018-02-10T00:00:00ZMild prenatal hypoxia-ischemia leads to social deficits and central and peripheral inflammation in exposed offspringhttp://hdl.handle.net/10468/5347
Mild prenatal hypoxia-ischemia leads to social deficits and central and peripheral inflammation in exposed offspring
O'Driscoll, David J.; Felice, Valeria D.; Kenny, Louise C.; Boylan, Geraldine B.; O'Keeffe, Gerard W.
Hypoxic-ischemic encephalopathy (HIE) resulting from intrauterine or perinatal hypoxic-ischemia (HI) is a leading cause of long-term neonatal neurodisability. While most studies of long-term outcome have focused on moderate and severe HIE in term infants, recent work has shown that those with mild HIE may have subtle neurological impairments. However, the impact of mild HI on pre-term infants is much less clear given that pre-term birth is itself a risk factor for neurodisability. Here we show that mild HI insult alters behaviour, inflammation and the corticosterone stress response in a rat model of pre-term HIE. Mild HI exposure led to social deficits in exposed offspring at postnatal day 30, without impairments in the novel object recognition test nor in the open field test. This was also accompanied by elevations in circulating adrenocorticotropic hormone and corticosterone indicating an exaggerated stress response. There were also elevations in il-1β and il-6 but not tnf-α mRNA and protein in the brain and blood samples. In summary we find that a mild HI exposure leads to social deficits, central and peripheral inflammation, and an abnormal corticosterone response which are three core features of autism spectrum disorder. This shows that mild HI exposure may be a risk factor for an abnormal neurodevelopmental outcome in pre-term offspring.
Sat, 20 Jan 2018 00:00:00 GMThttp://hdl.handle.net/10468/53472018-01-20T00:00:00ZFaecal microRNAs: indicators of imbalance at the host-microbe interface?http://hdl.handle.net/10468/5470
Faecal microRNAs: indicators of imbalance at the host-microbe interface?
Moloney, Gerard M.; Viola, Maria F.; Hoban, Alan E.; Dinan, Timothy G.; Cryan, John F.
The enteric microbiota is characterised by a balance and composition that is unique to the host. It is important to understand the mechanisms through which the host can maintain the composition of the gut microbiota. MicroRNAs (miRNA) are implicated in intercellular communication and have been isolated from bodily fluids including stool. Recent findings suggest that miRNA produced by the host’s intestinal epithelial cells (IECs) participate in shaping the microbiota. To investigate whether miRNA expression was influenced by the gut microbiota we measured the expression of miRNAs expressed by intestinal epithelial cells in faeces. Specifically, we measured miRNA expression in faeces from germ-free (GF) and conventional mice and similarly in a rat model of antibiotic-mediated depletion of the gut microbiota control rats. In adult male GF and conventional mice and adult Sprague Dawley (SD) rats were treated with a combination of antibiotics for 8 weeks; total RNA was extracted from faecal pellets taken at week 0, 2, 4, 6 week 8 and the expression of let-7b-3p, miR-141-3p, miR-200a-3p and miR-1224-5p (miRNAs known to be expressed in IECs) were measured relative to U6 at each time point using qRT-PCR. In GF animals the expression of let-7b, miR-141 and miR-200a in faeces was lower compared to conventional mice. Following antibiotic-mediated depletion of gut microbiota, rats showed two divergent profiles of miRNA expression. Following two weeks of antibiotic treatment, the expression of let-7b and miR-1224 dropped significantly and remained low for the remainder of the study. The expression of miR-200a and miR-141 was significantly higher at week 2 than before antibiotic treatment commenced. Subsequently, the expression of miR-200a and miR-141 decreased at week 4 and continued to decrease at week 6. This data demonstrates that miRNAs can be used as an independent, non-invasive marker of microbial fluctuations along with gut pathology in the intestine.
Thu, 21 Dec 2017 00:00:00 GMThttp://hdl.handle.net/10468/54702017-12-21T00:00:00ZDeficiency of essential dietary n-3 PUFA disrupts the caecal microbiome and metabolome in micehttp://hdl.handle.net/10468/5267
Deficiency of essential dietary n-3 PUFA disrupts the caecal microbiome and metabolome in mice
Robertson, Ruairi C.; Seira Oriach, Clara; Murphy, Kiera; Moloney, Gerard M.; Cryan, John F.; Dinan, Timothy G.; Ross, R. Paul; Stanton, Catherine
n-3 PUFA are lipids that play crucial roles in immune-regulation, cardio-protection and neurodevelopment. However, little is known about the role that these essential dietary fats play in modulating caecal microbiota composition and the subsequent production of functional metabolites. To investigate this, female C57BL/6 mice were assigned to one of three diets (control (CON), n-3 supplemented (n3+) or n-3 deficient (n3−)) during gestation, following which their male offspring were continued on the same diets for 12 weeks. Caecal content of mothers and offspring were collected for 16S sequencing and metabolic phenotyping. n3− male offspring displayed significantly less % fat mass than n3+ and CON. n-3 Status also induced a number of changes to gut microbiota composition such that n3− offspring had greater abundance of Tenericutes, Anaeroplasma and Coriobacteriaceae. Metabolomics analysis revealed an increase in caecal metabolites involved in energy metabolism in n3+ including α-ketoglutaric acid, malic acid and fumaric acid. n3− animals displayed significantly reduced acetate, butyrate and total caecal SCFA production. These results demonstrate that dietary n-3 PUFA regulate gut microbiota homoeostasis whereby n-3 deficiency may induce a state of disturbance. Further studies are warranted to examine whether these microbial and metabolic disturbances are causally related to changes in metabolic health outcomes.
Mon, 27 Nov 2017 00:00:00 GMThttp://hdl.handle.net/10468/52672017-11-27T00:00:00Z